ABSTRACT Recent transgenic mouse studies have highlighted impaired glymphatic function as potentially involved in the pathophysiology of Alzheimer's disease (AD). We learn from these studies that a reduced clearance of CSF, which carries A? and other waste products, needs to be considered in the development of amyloid plaques and possibly the pathophysiology of Alzheimer's. These observations complement well characterized trans- membrane A? clearance impairments in Alzheimer's. Lumbar puncture studies have confirmed an impaired clearance of A? to the CSF in AD patients. However, lumbar puncture studies do not distinguish between an impaired transport of A? across membranes from impairments in the bulk flow of CSF, which transports the A?. We developed the first non-invasive technology to quantify human CSF clearance. The technique uses PET to dynamically image a low molecular weight tau tracer with high brain penetrance, rapid clearance, and limited residual brain uptake. Our preliminary data demonstrate that after controlling for blood tracer levels, PET estimates of CSF clearance are highly reproducible within subject and across tau and amyloid PET tracers. CSF clearance achieves 89% accuracy for the diagnosis of AD. Most importantly, our results show that reduced tau tracer clearance measured at the ventricle and the cingulate gyrus (a major target for A? deposits) is closely associated with the magnitude of brain A? deposits as measured by PiB-PET. This strong inverse relationship between clearance and A? deposition is also found in normal elderly (NL) at both region and voxels levels. These observations justify our prospective longitudinal study of the relationship between CSF clearance, A? lesion progression, brain atrophy and cognitive decline. The study will enroll two age and gender matched NL elderly groups: amyloid-positive and amyloid-negative controls. Our preliminary data also revealed that the superior nasal turbinates are a CSF egress pathway in humans. This novel observation requires further anatomical and histological validation, which we propose to collect in an exploratory study. In sum, using a novel PET method to quantify the drainage of CSF from the human brain, we have the first opportunity to test the hypothesis that impaired CSF clearance facilitates A? propagation in preclinical Alzheimer disease.